ABSTRACT Alzheimer's and other tauopathies are medical problems growing to historical proportions that threaten the long term viability of medical care systems world-wide. Alzheimer's costs today are 1.2% of the US GDP, and growing as the population ages. Effective disease-modifying treatments have yet to be developed. A number of drugs in clinical testing target amyloid, but very few have been developed to target tau. We expect that like heart disease, cancer and HIV, effective Alzheimer's management will require combination treatment using multiple therapeutic modalities. Prior work by our research team has determined that part of the tau phenotype can be reduced using a histone deacetylase 6 (HDAC6) inhibitor, Tubastatin A (TA). This involved treatment of Tg4510 mice that develop tau deposits by 3 mo and forebrain atrophy by 6 mo of age. We treated mice from 5 to 7 mo and found improved behavioral performance and reduced total tau deposition. However, other components of the tau phenotype in this model were not significantly impacted. Here we propose to test whether an improved HDAC6 inhibitor, SW-100, can more completely rescue the tau phenotype in this mouse. SW-100 has a higher affinity, slightly longer half-life and substantially increased brain permeability than TA. SW-100 is a new HDAC6 inhibitor with selectivity similar to that of TA, but increased CNS penetration. SW-100 further lacks mutagenicity in the Ames test (in which TA was positive). Thus, we wish to evaluate if this compound, as well as a newly designed back-up analog, can more fully reverse the phenotype of the Tg4510 mouse by pursuing the three aims below. Aim 1. Prepare 4 new analogs of SW-100 as potential back-up compounds, and conduct HDAC isozyme testing, tubulin acetylation assays, and ADMET assays. Advance the best of these to animal studies in Aim 2. Aim 2. Conduct a dose range finding study of SW-100 and the best back-up compound from Aim 1 to identify a dose in mouse chow that causes maximal CNS impact and is well tolerated. Aim 3. Test SW-100 and the back-up analog from Aim 1 in Tg4510 mice starting at two ages to ascertain the extent to which these new chemical entities can retard the development of the tau phenotype, and whether benefits can be observed even after tau deposition has started. Assessments will thus be made of drug effects on cognition, histological tau deposition, and neurochemical tau accumulation. Any positive effects observed using these drugs after tau deposition would suggest benefit for people who already have dementia. There are several potential mechanisms by which HDAC6 may produce benefits. First, it may lead to more stable microtubules and enhance axonal transport through increased tubulin acetylation. Second, it may increase tau degradation in the proteasome through increased HSP90 acetylation. Third, it may inhibit tau aggregation through increased tau acetylation. We will monitor acetylation of each of these HDAC6 substrates to begin understanding the mechanism(s) most responsible for benefiting the tau phenotype in this model.